It has long been recognized that complete replication of the ends of eukaryotic chromosomes requires specialized cell components (Watson (1972) Nature New Biol. 239:197; Olovnikov (1973) J. Theor. Biol. 41:181). Replication of a linear DNA strand by conventional DNA polymerases requires an RNA primer, and can proceed only 5′ to 3′. When the RNA primer bound at the extreme 5′ ends of eukaryotic chromosomal DNA strands is removed, a gap is introduced, leading to a progressive shortening of daughter strands with each round of replication. This shortening of telomeres, the protein-DNA structures physically located on the ends of chromosomes, is thought to account for the phenomenon of cellular senescence or aging of normal human somatic cells in vitro and in vivo (Goldstein (1990) Science 249:1129; Martin (1979) Lab. Invest. 23:86; Goldstein (1969) Proc. Natl. Acad. Sci. USA 64:155; Schneider (1976) Proc. Natl. Acad. Sci. USA, 73:3584; Harley (1990) Nature 345:458-460; Hastie (1990) Nature 346:866-868; Counter (1992) EMBO J. 11:1921-1929; Bodnar (1998) Science 279:349-52).
The length and integrity of telomeres is thus related to entry of a cell into a senescent stage. Moreover, the ability of a cell to maintain (or increase) telomere length may allow a cell to escape senescence.
The maintenance of telomeres is a function of a specific DNA polymerase known as telomerase reverse transcriptase (TERT). Telomerase is a ribonucleoprotein (RNP) that uses a portion of its RNA moiety as a template for telomere repeat DNA synthesis (Morin (1997) Eur. J. Cancer 33:750). Consistent with the relationship of telomeres and TERT to the proliferative capacity of a cell, telomerase activity can be detected in highly replicative cell types such as stem cells. It is also active in an extraordinarily diverse set of tumor tissues, but is active in normal somatic cell cultures or normal tissues adjacent to a tumor (U.S. Pat. Nos. 5,629,154; 5,489,508; 5,648,215; and 5,639,613; Morin (1989) Cell 59:521; Shay (1997) Eur. J. Cancer 33:787; Kim (1994) Science 266:2011). Moreover, a correlation between the level of telomerase activity in a tumor and the likely clinical outcome of the patient has been reported (U.S. Pat. No. 5,639,613; Langford (1997) Hum. Pathol. 28:416).
Telomerase activity has also been detected in human germ cells, proliferating stem or progenitor cells, and activated lymphocytes. In somatic stem or progenitor cells, and in activated lymphocytes, telomerase activity is typically either very low or only transiently expressed (Chiu (1996) Stem Cells 14:239; Bodnar (1996) Exp. Cell Res. 228:58; Taylor (1996) J. Invest. Dermatol. 106:759).
The preceding summary is intended to introduce the field of the present invention to the reader. The cited references in this application are not to be construed as admitted prior art.